Bordetella pertussis is the causative agent of whooping cough. Introduction of killed whole-cell B. pertussis (wP) vaccines in the 1940s has been successful in reducing the morbidity and mortality due to whooping cough in children and infants (on the World Wide Web at cdc.gov/vaccines/pubs/pinkbook/downloads/pert.pdf; Bisgard, K. M. on the World Wide Web at cdc.gov/vaccines/pubs/pertussisguide/downloads/chapter1.pdf. 2000; Edwards, K. M. & Decker, M. D. Pertussis vaccines. In Vaccines (eds. Plotkin, S. A., Orenstein, W. A. & Offit, P. A.) Elsevier Health Sciences, 2008. 467-517; this textbook is hereinafter referred to as “Vaccines, Plotkin 2008”). Nevertheless, worldwide, pertussis remains an important problem in children. Estimates from the WHO suggest that in 2008 about 16 million cases of pertussis occurred, and that about 195,000 children died from this disease.
Since the 1990s wP vaccines have been replaced by acellular pertussis (aP) vaccines in most high-income and more recently also in some middle-income countries. Acellular pertussis vaccines induce relatively fewer side-effects compared to wP vaccines that are associated with a high risk for fever (>38° C.), reactogenicity at the injection site and, although to a lesser extent, convulsions and hypotonic-hyporesponsive episodes [Zhang, Cochrane Database Syst Rev 2011).
One to two decades after introducing aP vaccines, a rise in pertussis notifications in adolescents and adults has been reported by several countries, including the US, UK, Australia, Norway and the Netherlands. Possible explanations include improved diagnostics and surveillance, adaptation of circulating B. pertussis strains to vaccines, and/or increased waning immunity associated with aP vaccines (Tanaka, Jama 2003, 290: 2968-2975; Satoh, Comp Immunol Microbiol Infect Dis 2010, 33: e81-88; Zepp, Lancet Infect Dis 2011; De Greeff, PLoS One 2010: e14183; Tan, Pediatr Infect Dis J 2005, 24(5 Suppl): S10-18).
Currently, all licensed aP vaccines consist of minimal one, but mostly multiple, up to a maximum of five (detoxified) B. pertussis virulence factors. All aP vaccines contain pertussis toxoid (PT). Multicomponent aP vaccines at least include PT and the B. pertussis surface adhesin filamentous hemagglutinin (FHA). With increasing valency further one or more of the adhesins pertactin (PRN) and fimbriae type 2 and type 3 (FIM2 and FIM 3, together referred to as FIM or FIM2/3 herein) are present (Edwards, In: Vaccines, Plotkin, 2008. 467-517).
WO 96/34883 describes doses of 1-10 μg of FIM per human dose, with doses of 10 and 5 μg per human dose in an aP vaccine exemplified, while only doses of 5 μg per human dose were actually tested, and the tested vaccines were considered efficacious.
It is generally believed that aP5 vaccines (acellular pertussis vaccines with the five components PT, FHA, PRN, FIM2/3; DTaP5 are aP5 vaccines further comprising tetanus toxoid and diphtheria toxoid) are the most effective aP vaccines currently available. The individual amounts of the aP components present in commercially available registered aP5 vaccines are (in microgram per human dose): 2.5-20 for PT, 5-20 for FHA, 3 for PRN and 5 for FIM.
In several of the acellular pertussis vaccine efficacy trials conducted in Europe in the mid-1990s, efforts were made to determine immune correlates of protection for the individual aP vaccine components. Using data from the Swedish DTaP5 (PT+FHA+PRN+FIM2/3) trial a statistically significant correlation between clinical protection and the presence in pre-exposure sera of IgG antibodies against PRN, FIM2 and PT, but not to FHA, were demonstrated (Storsaeter, Vaccine 1998, 16: 1907-1916). FIM3 appears to be a nonprotective component within DTaP5 (Poolman, Expert Reviews Vaccines 2007, 6: 47-56).
Sera collected from subjects from a vaccine trial in Germany allowed estimation of the specific levels of antibody to PT, FHA, PRN and FIM2 that correlated with protection, which showed that only antibodies against PRN, and PT were significantly associated with protection (Stehr, 1998, Pediatrics 101: 1-11; Cherry, 1998, Vaccine 16: 1901-1906). In addition, pre-clinical studies have shown that the addition of PRN enhances the level of protection conferred by vaccines that contain PT and FHA in a murine intranasal infection model (Guiso, 1999, Vaccine 17: 2366-2376; DeNoel, 2005, Vaccine 23: 5333-5341) and that antibodies to PRN were crucial for opsonophagocytosis of B. pertussis (Hellwig, 2003, JID 188: 738-742). Together these data indicate that PT and PRN are the main protective antigens in current acellular pertussis vaccines.
As part of a prospective aP vaccine efficacy trial, protective IgG against PT, FHA, PRN and FIM2/3 was measured in consecutive serum samples obtained from participants over an 18-month period. Over the 18-months the percent decay in IgG against PT was strongest (73% reduction in geometric mean IgG titer) and was significantly higher than the percent reduction in antibodies against PRN, FHA and FIM. In contrast, IgG antibody to PRN had the lowest decay rate (56% reduction in geometric mean IgG titer) (Le, 2004, JID, 190: 535-544).
Combining the two observations that 1) PT and PRN are the main protective antigens in aP vaccines and 2) that antibodies to PT have a significantly higher decay rate than antibodies to PRN, highlights that anti-PRN antibodies are crucial in providing aP-mediated long-term protection against B. pertussis infection.
However, an emergence of B. pertussis strains not expressing PRN has been observed in the last few years around the world, for example, in France, Japan, the Netherlands, the USA, Finland, Norway and Sweden (Bouchez, 2009, Vaccine 27: 6034-41; Hegerle, 2012, Clin. Microbiol. Infect. 18: E340-346; Otsuka, 2012, PloS One 7: e31985; Advani, 2013, J. Clin. Micro 51: 422-428). A recent study in the US showed that 11 out of 12 isolates of B. pertussis cultured from specimens from children hospitalized in Philadelphia during 2011 and 2012 were in fact PRN-negative (Queenan, 2013, N Engl J Med. 368: 583-4). Whether this strain adaptation is primarily vaccine-driven is currently not known. It is possible that these PRN-negative strains can escape vaccine induced immunity, especially when anti-PT titers have declined, and that this has contributed to the observed increase in B. pertussis disease.
The currently licensed and marketed aP vaccines thus appear insufficiently efficacious, especially against the newly emerging PRN-negative strains.